Clinical Pharmacy Introduction to Clinical Pharmacy, Concept of clinical pptx
L'eterogeneità della pancreatite cronica - Gastrolearning®
1. Università di Verona AOUI di Verona
Dipartimento di Istituto del Pancreas
Medicina
L’eterogeneità
della pancreatite
cronica
Italo Vantini
2. Conoscere una malattia - 1
• La conoscenza delle connotazioni di una
malattia consente di fornire:
– una descrizione utile per l’inquadramento
classificativo (nosologico) (che cosa è)
• Etiopatogenetica
• Clinica
• Anatomopatologica
• Fisiopatologica
– un “nome”’per la sua identificazione
nosologica (condivisione di come si chiama)
3. Conoscere una malattia - 2
• Una diagnosi
– Matching, illness script, exemplars
– Percorsi probabilistici
– Criteri, strumenti, percorsi, processi
• La diagnosi non è “tanto” l’inserimento del
paziente in una “casella nosologica, ma un
giudizio basato su dati e criteri utili per
assumere decisioni operative ai fini della:
• Prognosi
• Terapia
4. In principio…
Sarles H, Sarles JC, Camatte R, Muratore
R, Gaini M, Guien C, Pastor J, Le Roy
F
Observations on 205 confirmed cases of acute
Gut 1965; 6: 545-59.
5. Chronic pancreatitis
Chronic process characterized
by inflammatory and fibrotic
changes of the pancreas.
Irreversible nature of structural
changes and progressive
functional impairment
6. Chronic pancreatitis
Fibrosis of the pancreas
Damage to the acinar tissue
morphologically Changes in ductal system
• Calcifications
7. Chronic pancreatitis: progressive
parenchymal changes
Normal pancreas
Moderate changes more or less
scattered troughout the pancreas
Advanced changes (fibrosis)
11. Pain in chronic pancreatitis
Clinical pictures
Type 1pain recurrent with lasting
pain-free intervals
Type 2 pain : frequent, persisting,
disabling pain
PATHOPHYSIOLOGY
• Acute inflammation
• Ischemia
• Increased intraductal and parenchymal pressure
• Mechanical compression (e.g. pseudocyst)
Pancreatic neural remodelling and neuropathy
12. Chronic pancreatitis
• Recurrent or persistent
clinically pancreatic pain
Changes in ductal system
• Fibrosis of the pancreas
morphologically • calcification
• Deterioration in
functionally pancreatic function
(exocrine and endocrine)
13. Frequency of painful relapses/year in 199
patients with chronic pancreatitis
(non-operated upon) followed up to 20 years
Prevention and treatment percentiles
Treatment of 25°
early
treatment of advanced
relapsing exocrine failure
late
of painful relapses or persisting pain and secondary 50°
5 and complications
diabetes 75°
4
N. painful
relapses
in time
3
on
sfuncti
and dy
2
n
1
Calcificatio
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
25°
years since clinical onset
Scuro LA et al , Am J Gastroenterol 1983; 78: 495-501.
Ammann RW et al. Gastroenterology 1984, 86: 820-8..
17. Chronic Pancreatitis
(“old concepts”) - 1
a single and distinct entity
a well defined epidemiological
and clinical pattern
Male/female 4:1; age onset 47 year old
alcoholic in origin
(in Western Countries)
Differs from Acute Pancreatitis
(etiology, clinical outcome,prognosis)
Acute and chronic pancreatitis are two distinct entities
19. Chronic Pancreatitis
Alcohol abuse in more recent studies
100
90
80
% of patients
70
60
50
40
30
20
10
0
Italy 2009° India 2008* USA 2008^ China 2009"
893 pts 1033 pts 540 pts 2008 pts
° Frulloni L et al, PanCroInfAISP, Dig Liv Dis 2009; 41: 311-317
* Balakrishnan V et al, J Pancreas, 2008; 9: 593-600
^ Withcomb DC et al, NAPS2, Pancreatol, 2008; 8: 520-531
” Whang LW et al, Chinese CPSG, Pancreas, 2008; 38:248-54.
20. Smoking and chronic pancreatitis:
a meta-analysis
Andriulli A, Botteri E, Almasio PL, Vantini I, Uomo G, Maisonneuve P: Smoking as a
cofactor for causation of chronic pancreatitis. Pancreas 2010; 39: 1205- 1210
21. Smoking and pancreatic calcification
Giving-up smoking within 5
years since onset of CP reduces
the risk of developing pancreatic
calcifications
Talamini G et al
Pancreas. 2007 ;35:320-6.
Talamini G, Bassi C, Falconi M, Sartori N, Vaona B, Bovo P, Benini L, Cavallini G, Pederzoli P, Vantini I
Smoking cessation at the clinical onset of chronic pancreatitis and risk of pancreatic calcification.
22. Pancreatic acinar cell damage in response to cigarette smoke
components : sensitization to acinar cell injury, that can be
worsened by alcohol consumption
similar
Trypsinogen to
but not PSTI experimental
acute
pancreatitis
Cytoplasmic
oxidative swelling
stress and
lipid
perossidation
Alexander M et al Pancreatology; 2011: 11: 469-74
24. Chronic Pancreatitis
(“concepts”) -2
a single and distinct entity
alcohol and smoke interact as risk
factors
increased risk of pancreatic cancer
a single clinical pattern, though
evolving in time
25. Epidemiological and clinical features of
chronic pancreatitis: the identikit
• Males (80%)
• 45 year old at the clinical onset
• Alcohol abusers (40-60%)
• Smokers in (> 80%)
• Pancreatic calcification (20% at onset)
• Dilation/changes of pancreatic duct system
• Painful relapses
• Progressive pancreatic failure (exocrine and
endocrine)
26. Chronic pancreatis
principles of therapy-2
• Prevention of relapses
– Alcohol withdrawal in an early stage
• Reduction in the risk of pancreatic calcifications
and of the progression of the disease
– Smoking withdrawal
• Reduction in the risk of pancreatic cancer (?)
– Smoking withdrawal
• Treatment of relapses
– Treatment of acute flares (starvation, IV fluids, analgesic
drugs)
• Treatment of disabling and severe pain and/or of
complications
– Surgery (drainage or resection) (not “untimed”)
associated with alcohol withdrawal
• Treatment of exocrine failure
28. a “new” pancreatitis ?
men
heavy alcohol drinkers
heavy smokers
calcification (90%)
dilation of the pancreatic duct (80%)
aggressive painful pancreatitis, often
disabling (> 50%)
vomiting, jaundice
30. EUS findings
Normal
cyst Duodenal
Wall
Thickened
duodenal wall
cyst
31. Cystic dystrophy of the duodenal wall
The “groove” area
Groove C Groove
C BD
D W
P
D = duodenum P = papilla of Vater
BD = common bile duct W = Wirsung’s duct
C = cyst
32. CYSTIC DYSTROPHY OF DUODENAL WALL
A bud of dorsal pancreas,
associated to the Santorini's duct,
entrapped within the duodenal wall
during organogenesis
33. Paraduodenal pancreatitis
(cystic or solid duodenal dystrophy)
almost all men
almost all heavy alcohol abusers
almost all smokers
calcification (90%)
disabling painful relapses
vomiting, jaundice (at onset)
34. Main clinical features in different types of
chronic pancreatitis
Alcoholic
Hereditary
Paraduod.
Obstructive
Painless
AIP
35. Alcoholic pancreatitis and paraduodenal
pancreatitis (PDP)
• PDP pancreatitis shares the same risk factors and
similar epidemiological and clinical pattern of alcoholic
pancreatitis
• Morphologically is a distinc form of CP
• PDP clinically behaves a severe clinical form of
alcoholic pancreatitis
• Though alcohol withdrawal can induce some clinical
improvement, more than 50% of the patients are
eligible for surgery because of invalidating pain and/or
duodenal obstruction
• It is probable that old series of patients formerly
classified as alcoholic pancreatitis were in fact PDP
36. cysts of the duodenal wall and chronic pancreatitis
Dilation of Wirsung
Head calcifications
D Groove
Zone
D = duodenal lumen
W=Wirsung’s duct
38. Obstruction and chronic pancreatitis
• Several experimental data on different
animal models show that chronic
pancreatitis cannot develop, irrespective
of the type of the experimental damage,
without an obstruction of the duct system
• Periductal inflammation can lead,
together with stellate cells activation, to
periductal fibrosis that can induce
changes in the pancreatic duct system
40. Following an acute pancreatitis
Chronic pancreatitis can be the
consequence of a necrosis-
Acute pancreatitis 8 months before
fibrosis change, leading to
obstruction of pancreatic duct
system, and then to inflammatory
and fibrotic changes.
Acute necrotizing
pancreatitisan acutelead of
can attack to
chronic pancreatitis before
pancreatitis 6 months
41. Acute pancreatitis: frequency of chronicization
(19/88=22%)
Lankish PG et al., Am J Gastroenterol, 2009; 104: 2796-2805
42. Acute pancreatitis: frequency of relapses
following the first episode
(alcoholic vs. non-alcoholic pancreatitis)
40%
32%
15%
10%
Lankish PG et al. Am J Gastroenterol, 2009; 104: 2796-2805
43. “obstructive”
pancreatitis
Factors (different from
slow-growing tumors) hampering
the pancreatic outflow can
trigger a process leading to
obstructive pancreatitis
A “dysfunction” at the Oddi’s sphincter (SOD)
can lead to chronic pancreatitis obstructive
Oddi’s sphincter inflammation with altered outflow
can “trigger” chronic pancreatitis
An obstacle to the pancreatic outflow can be associated with
relapsing pancreatitis without evidence of ductal changes
45. Obstruction is the most frequent
associated factor in women (46%)
DLD 1999; 41. 311-17
46. Main clinical features in different types of
chronic pancreatitis
Alcoholic
Hereditary
Paraduod.
Obstructive
Painless
AIP
47. Pain in chronic pancreatitis
Clinical pictures
Type 1pain recurrent with lasting
pain-free intervals
Type 2 pain : frequent, persisting,
disabling pain
PATHOPHYSIOLOGY OF PAIN IN
“OBSTRUCTIVE PANCREATITIS”
Increased intraductal-parenchymal
pressure caused by decreased drainage of
pancreatic juice into the duodenum
•
48. Uncomplicate chronic pancreatitis
- Indication for surgery -
The rationale of drainage surgery is a decompression within the
ductal system and reduction in pain in a substantiaòproprtion of patients
50. Large stone in the duct
ERCP following sphincterotomy,
ESW and fragment extraction
51. Surgery (pancreatojejunostomy) vs. endoscopy
(sphincterotomy) in chronic pancreatitis
Djuna L Cahen et al
NEJM 2007; 356: 676-84
Djuna L Cahen et al
but in 6/7 evaluable patients
submitted to rescue surgery,
it was uneffective
52. Who are the main clinical and morphological
features of the patients with good results of
drainage surgery and poor after endotherapy ?
• Advanced chronic pancreatitis
In advanced chronic pancreatitis
• with symptoms and distal
Distal obstruction
• obstruction, drainage surgery
Calcifications (> 90% of the cases)
is superior to endoscopic
• Severe, recurrent pain
therapy
• Not too enlarged head of the
pancreas
53. Who are the patients with chronic pancreatitis in which the
endoscopic therapy seems to be more effective ?
• single distal obstruction
• single distal stone
• short duration of the disease
• more aggressive, repeated stenting strategy
– Pancreatic sphincterotomy
– Stricture dilation
– Repeated stenting
– Stone removal
Farnbacher et al Gastrointest Endosc 2002; 56: 501-59
Costamagna G et al Endoscopy 2006; 38: 254-59
Dumonceau JM et al ESGE guidelines- Endoscopy 2012, 44. 784-96
54. For treating uncomplicated chronic pancreatitis
(aimed at relieving pain) ESGE recommends
ESW/ERCP at the first-time interval option.
The clinical response should be evaluated
at 6-8 weeks.
If it is unsatisfactory the case
should be discussed in a multidisciplinary
team.
Surgical options should be considered,
in particular in patients with a predicted poor
outcome after endosopic therapy (RG B)
55. Candidate parameters for selecting patients for
appropriate treatment and timing
(a multidimensional approach)
• Aethiology, natural history
• Duration of the disease (stage)
• Clinical features (pain type, complications) and QOL scores
• Morphological assessment
– Main pancreatic duct and secondary branches changes
– Distal stenosis (main duct, Santorini)
– “Dominant” duct stricture
– Single or multiple obstructions-strictures
– Upstream dilation (+/-)
– Stone (single, distal, multiple)
– Ductal scars (necrosi/fibrosis) However, pain
can persist also following
– Complications effective treatment of stricture,
• Technical aspects and aggressive strategy or it can subside also
if the stricture is not disappeared
56. Pain treatment: appropriate patient selection
• A proper patient selection is of vital importance in the
indication and in the outcome of treatment, in particular
case of endoscopic and surgical therapy
• A more aggressive endoscopic strategy probably will
give better results in properly selected patients
• Surgery should be timed and tailored to the clinical
features and risk assessment, morphological pictures,
and the best as possibile assessment about the
presumptive origin of pain. Combination surgery should
be considered
59. Frequency of painful relapses/year in 199
patients with chronic pancreatitis
(non-operated upon) followed up to 20 years
Endoscopy-Surgery
percentiles 25°
early
Endotherapy
advanced
Medical treatment
Medical
late
Medical treatment treatment 50°
5
75°
4
N. painful
relapses
in time
3
on
sfuncti
and dy
2
n
1
Calcificatio
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
25°
years since clinical onset
Scuro LA et al , Am J Gastroenterol 1983; 78: 495-501.
Ammann RW et al. Gastroenterology 1984, 86: 820-8..
60. 25 years ago…..
• Amman RW et al Gastroenterology 1986
– in chronic pancreatiis early surgery is
associated with a poor cinical outcome
– the natural history of CP indicates that in
almost 2/3 of the patients pain
spontaneously subsides in long-term
evolution
– Commentary (Gastronterology 1986)
• “The patient patient and the impatient
surgeon”
63. Gene-mutation associated pancreatitis
Main features of Hereditary Pancreatitis
Hereditary-Familial
one or more relatives of the same familial kindred
affected, at different or at the same generation,
No other risk factor of pancreatitis (complete work-up)
Juvenile onset < 10 years (< 20 years)
Recurrent episodes of mild pancreatitis
Progression of pancreatic calcifications
Slow progression toward pancreatic failure
Survival rate comparable to that of the general
population
64. Cumulative risk of cancer in patients with
Hereditary Pancreatitis
(smokers vs. non smokers)
smokers
non-smokers
Lowenfels AB et al JAMA 2001; 286:169-70
65. pancreatite associata a mutazione del
CFTR
Pancreatite associata a
mutazione del gene SPINK 1
66. SPINK1
Chronic pancreatitis associated with gene
mutation
SPINK1 Bull-eye sign SPINK1 Bull-eye sign
non smokers
CFTR
smokers
Graziani R. et al. Abdominal Radiology, 2010; 115: 885-88
Frulloni L, et al. Pancreas. 2008:371-
71. Chronic pancreatitis and gene mutations
• Mutation in PRSS1 is present in ¼ of patients
with juvenile-type chronic pancreatitis
• Up to 30% of idiopathic pancreatitis have a
mutation in the CFTR allele vs. 3-5% in the
general population, though a single mutation
alone cannot trigger pancreatitis
• 20-30% of Hereditary Pancreatitis do not have
PRSS1 mutation
• Mutation in PRSS1 is found in 20% of subjects
who do not have any sign of pancreatitis
(carriers)
Rebours V et al DLD 2012; 44: 8-15
72. Pancreatite associata ad alterazioni geniche
Esordio clinico = Pancreatite acuta
SI (87%) NO (13%)
Età all’esordio p = 0.005 Età all’esordio
28 ± 14 anni 44 ± 18 aa
CFTR-S = 30 ± 14 anni
CFTR-S = 30 ± 14 anni Clinica all’esordio:
Clinica all’esordio:
CFTR-D = 20 ± 12 anni
CFTR-D = 20 ± 12 anni Dolore aspecifico (6)
Dolore aspecifico (6)
SPINK1 = 24 ± 14 anni
SPINK1 = 24 ± 14 anni Dispepsia (2)
Dispepsia (2)
p = 0.027
p = 0.027 Ittero (1)
Ittero (1)
Altra patologia (2)
Altra patologia (2)
STORIA NATURALE DELLA PANCREATITE 10 di 11 pazienti
10 di 11 pazienti
ASSOCIATA A MUTAZIONI GENICHE = PC all’esordio
Giulia De Marchi = PC all’esordio
Tesi di Laurea, 2011
73. Long time ago….
“Why should the
pancreas be the only
human organ not
involved by an
Ludovico Antonio Scuro
autoimmune process?”
1924 – 1989
74. Autoimmune pancreatitis
• Described by H. Sarles in 1961 yet,
• More than 900 papers published (most since
’90s)
• Accounts for
– 4-6 % of all the patients with chronic pancreatitis
referring to a terziary centre and for
– about 20-40 % of idiopathic chronic pancreatitis
• Its aethiology is still unknown
antibodies: CA II, Lactoferrin, SPTI antibodies
(against host antigens); genetics: association with
haplotype DRB1 0405 DQB1 0401; Polymorfism of
Cytotoxic Lymphocyte-associated antigen-4 49A
75. Autoimmune Pancreatitis
Main Clinical Features
No drinker and no smoker patients
Frequent association with other
autoimmune diseases
Asymptomatic jaundice at onset
(particularly in focal type)
“Atypical” pancreatitis at onset
(particularly in diffuse type)
77. From Zamboni G et al
Type 1
Autoimmune Pancreatitis is a chronic
pancreatitis
LP . periductal inflammation
IgG4 positive plasmacells
Duct desctruction and narrowing
Storiform fibrosis
80. Narrowed and irregular duct in autoimmune
chronic pancreatitis
Associated with
a clinical picture
81. Autoimmune pancreatitis
Focal and mass forming
Early arterial phase
Focal
Mass forming jaundice
University of Verona: Dpt. of Radiology
82. Mass forming AIP
ry
a to
d
an
m
The problem is not to confirm
histologically AIP, but to exclude cancer
by US or EUS-guided biopsies
University of Verona: Dpt. of Radiology
84. Pancreatite acuta lieve seguita
Reperto da precoce ricorrenza lieve
di base e persistenza di moderata
elevazione degli enzimi
Dopo terapia
steroidea
01-2009
02-2009
86. ICDC Autoimmune pancreatitis type 1: cardinal
diagnostic criteria and levels of reliability
Shimosegawa T et al, Pancreas, 2011: 40: 352-358
87. ICDC Autoimmune pancreatitis type 2:
cardinal diagnostic criteria and levels of reliability
Shimosegawa T et al, Pancreas, 2011: 40: 352-358
88. Tipi di pancreatite autoimmune
dopo completo work-up (ICDC)
92 Pazienti
Tsukasa Ikeura et al 2013, submitted
89. Three types of AIP: overlaps among
diagnostic features
AIP type 2
AIP type 1
AIP NOS
90. Phil A Hart et al: Long-term outcomes of autoimmune pancreatitis:
a multicentre, international analysis
Gut Online First, published on December 11, 2012 as 10.1136/gutjnl-2012-30361
Type 1
23 institutions 1064 ICDC
978
10 countries patients criteria
Type 2
86
*
Type 1
31%
Relapse rate (> in IgG4 –related sclerosing cholangitis)
Type 2
9%
* retreatment with steroids was equally effective
91. Phil A Hart et al: Long-term outcomes of autoimmune
pancreatitis:a multicentre, international analysis
Gut Online First, published on December 11, 2012 as 10.1136/gutjnl-2012-30361
92. Chronic pancreatitis
paraduodenal
alcoholic
AIP
geneti
c obstructive
idiopatic
painless
Eterogeneity
and ovelap
93. Classificazioni della pancreatite cronica
• Etiologia, clinica e morfologia (nosografica)
– Marsiglia 1963
– Cambridge, 1983
– Marsiglia 1984
– Marsiglia-Roma 1988
• Per stadio di malattia (early, late, advanced)
– Chari ST, Singer MV Scand J Gastroenterol 1994; 29: 949-60
• Per fattori di rischio
– TIGAR-O Etemad B, Whitcomb DC. Gastroenterology. 2001
• Per approccio operativo-terapeutico
– Cavallini G, 2000 (“classificazione di Verona”)
• Per probabilità di diagnosi (clinica, imaging, funzione, istologia)
– Zurich 1997
– JAP 1997
• Per combinazione di clinica, probabilità di diagnosi, stadiazione,
severità + score
– M-ANNEHEIM (Schneider A, Lohr JM, Singer MV. J Clin
Gastroenterol 2007; 42: 101-119)
94. M-ANNHEIM
classification of chronic pancreatits
Risk Probabaility of
• EZIOLOGICO
factors the diagnosis
Classification by
Clinical
Severity features and
stage
Schneider A, Löhr JM, Singer MV.The M-ANNHEIM classification of chronic pancreatitis: introduction of a unifying
classification system based on a review of previous classifications of the disease.J Gastroenterol. 2007; 42:101-19.
95. Chronic pancreatitis
- classifications and operative needs -
• Nosographic classification
• Diagnostic matching with illness scripts,
exemplars,categories
• Operative classification
• Operative diagnosis targeted to decisions
• Complexity/undefined aspets/variation in time
• Diagnosis (disease) reliability : defined, probable,
possible, undefined
97. EBM
Evidence Level (EL) of the literature
information/source of the
statements
40
35
30
25
% of the
20
statements
15
10
5
0
1 2 3 4 5
According to Oxford Centre for Evidence Based Medicine
98. EBM
Recommendation strenght of the statements,
and agreement (consensus) rate
40
35
30
25
% of the
20
statements
15
10
5
0
A B C D
According to Oxford Centre for Evidence Based Medicine
83% of the statements: agreement rate*> 80%
* Agreement rate: “strongly agree or with minor reserve”
99. In principio…
Sarles H, Sarles JC, Camatte R, Muratore
R, Gaini M, Guien C, Pastor J, Le Roy
F
Observations on 205 confirmed cases of acute
Gut 1965; 6: 545-59.
And the main but now old concepts were that cronic pancreatitis is (leggi)
And the main but now old concepts were that cronic pancreatitis is (leggi)
Pathologists told has that there is a particular type of pancreatitis arise from the duodenal wall. In duodenal wall there are islet of pancreas normally. In patients who drank a lot, this islet became inflammed inside the duodenal wall and later may grow and extend toward
cresci
Pathologists, first of all prof. Kloppel, teach us that in autoimmune pancreatitis the histologic findings are typical for the disease. We can see inflammatory infiltration in to the pancreas, mainly around the ducts, with rupture of the basal membrane and secondary destruction of pancreatic ducts.
… . like in this case, presents an enlargement of the pancreatic head, but without any sign of vascular or soft tissue infiltration. This was the first control. Once the diagnosis is suspected, the second examination, ..